CN1470235A - Animal model of schizophrenia and its medicine sorting platform - Google Patents
Animal model of schizophrenia and its medicine sorting platform Download PDFInfo
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Abstract
The invention provides a schizophrenic animal model, the drug screening platform, and the screening medhod of the drug curing psychosis. The little rat model and the human schizophrenia surely have the relativity. Based on the platform, it can be used to screen new drug and develop other cures.
Description
Technical field
The present invention relates to Animal Behavior Science and drug screening field, more specifically, the present invention relates to a kind of animal model of schizophrenia and medicine sorting platform thereof, and the method for utilizing this platform screening treatment psychosis medicine.
Background technology
Psychosis especially schizophrenia is that since modern also is the disease that lacks diagnostic method and treatment means most for thinking that influences the people and the most threatening power of ability to work simultaneously as the pathological changes that influences cranial nerve senior thought function.At present the mechanism to the molecular cytobiology of its pathogeny and morbidity is short in understanding.
The foundation of animal model of schizophrenia is the primary key of schizophrenia mechanism and drug research thereof.Though researcheres are also attempted to set up some animal models and are used for psychotic research for a long time, but since psychotic complexity with and pathogenesis indeterminate, make psychotic mechanism research be absorbed in vicious cycle: limited psychosis relevant knowledge has limited the foundation of animal model, does not have good animal model directly to influence the psychosis Study on Pathogenesis again.Recently careful day by day along with neuroendocrinology, neuro chemistry, development of molecular biology and clinical investigation, certain theoretical basis that made establishing of psychosis animal model, its method also begin from single interference animal living enviroment as: noise stimulate, high light stimulates, destroy life rhythm etc. to diversified development, as methods such as drug-induced, gene knockouts.
Yet, still do not have gratifying animal model of schizophrenia up to now.Therefore the current new animal model of schizophrenia of exploitation that presses for, in order to the especially schizoid pathogenic factor of research psychosis, biology mechanism and related drugs exploitation.
Summary of the invention
Purpose of the present invention just provides a kind of new animal model of schizophrenia and preparation method thereof.
Provide medicine sorting platform in another purpose of the present invention based on this animal model of schizophrenia.
In a first aspect of the present invention, a kind of method of setting up schizophrenia mammal model is provided, it comprises step:
Give N-methyl D-aspartic acid (NMDA) noncompetitive receptor antagonist of described administration schizophrenia effective dose, preferably, described antagonist is 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt.
In a preference, use 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt by intraperitoneal injection.
In a second aspect of the present invention, a kind of method of screening the psychosis medicine is provided, comprise step:
(a) material standed for is applied to mammal with 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt;
(b) observe mammiferous schizophrenia characteristic behavior, wherein, the decline of the schizophrenia characteristic behavior frequency of occurrences and/or amplitude just represents that this material standed for is the psychosis medicine.
In a preference, described schizophrenia characteristic behavior comprises strides running property of lattice and repeated unusually.
In another preference, in the step (a), also comprise material standed for or MK801 are applied to mammal respectively separately.
In another preference, in the step (a), the amount of application of 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt is a 0.05-5 mg/kg body weight.
Description of drawings
Stride the lattice curve of running behind Fig. 1 BALB/c mouse injection various dose MK801.
Unusual repetitive curve behind Fig. 2 BALB/c injection various dose MK801.
Stride the lattice curve of running behind Fig. 3 C57BL/6 injected in mice various dose MK801.
Unusual repetitive curve behind Fig. 4 C57BL/6 injected in mice various dose MK801
What Fig. 5 Risperidone acted on the schizophrenia disease mouse model strides the lattice curve of running.Among the figure, Sal represents saline, and Ris represents Risperidone, and MK represents MK801.
Fig. 6 Risperidone acts on the unusual repetitive curve of schizophrenia disease mouse model.Among the figure, Sal represents saline, and Ris represents Risperidone, and MK represents MK801.
The specific embodiment
The present inventor, through for many years extensive and deep research, find to adopt drug-induced method, as passing through to mouse peritoneal injection MK801, the performance degree that running property of lattice (locomotion activity) and repeated unusually (stereotypy) two indexs are measured the similar the symptoms of schizophrenia of mice after the administration is striden in selection, thereby set up similar schizoid mouse model, schizoid symptom is quantized first.And set up medicine sorting platform on this basis.
As used herein, term " MK801 " is 5-methyl dihydro-dibenzo cycloheptene imido maleic acid (or its salt, especially pharmaceutically acceptable salt), it is N-methyl D-aspartic acid (NMDA) noncompetitive receptor antagonist, can make mice produce similar schizoid symptom.
As used herein, term " schizophrenia effective dose " refers to cause that mammal produces the dosage of schizoid symptom or behavior.Depend on used laboratory animal, the schizophrenia effective dose can be different.Those skilled in the art can be determined by experiment the schizophrenia effective dose.For MK801, the schizophrenia effective dose is generally about 0.05-5 mg/kg body weight, preferably about 0.1-2.5 mg/kg body weight; More preferably about 0.15-2 mg/kg body weight, about best 0.3-1.0 mg/kg body weight.
As used herein, term " schizophrenia characteristic behavior " refer to can the schizoid symptom of mammiferous representative behavior.Representational example comprises (but being not limited to): stride the quickening of running property of lattice, and the appearance of repeated unusually (stereotypy) and increase, for example turn-take, significantly shake the head in original place among a small circle, roll about in the original place etc.
In the methods of the invention, at first be preparation schizophrenia animal pattern, N-methyl D-aspartic acid (NMDA) the noncompetitive receptor antagonist such as the MK801 that are about to the schizophrenia effective dose are applied to mammal.Application process is not particularly limited, and preferable methods comprises (but being not limited to): lumbar injection, intravenous injection, intramuscular injection etc.
Be applicable to that animal of the present invention can be a mammal, for example rodent, Primate etc., preferable animal is a rodent, better animal is mice, rat.
In the present invention,, the control animals that is used for comparison be should be provided with, positive control and negative control comprised in order to compare better.Usually, the example of control animal comprises the animal of having injected normal saline, the animal (positive control) of having injected the animal of MK801, only having injected the animal of candidate substances and having injected MK801 and known drug simultaneously.
Can be used for animal behavior of the present invention and comprise any behavior that can reflect the animal the symptoms of schizophrenia.Should be understood that for different laboratory animals, selected animal behavior can be different.For example, for mice, representational animal behavior comprises (but being not limited to): stride running property of lattice (locomotion activity) and repeated unusually (stereotypy) etc.
The inventor has carried out checking or screening to known drug or unknown materials on the basis that has made up above-mentioned mice schizophrenia drug screening platform, obtained gratifying result.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example usually according to normal condition, or carries out according to the condition that manufacturer advises.
Embodiment
Materials and methods
1. material
Reagent: MK801, Risperidone (Risperidone), GNTI[dihydric salt hydrochlorate (dihydrochloride) 11/2H
2O, molecular formula C
27H
29N
5O
32HCl, molecular weight 544.48]
Instrument: the Flex-Field System Animal Behavior Science surveillance that U.S. SD company produces, shoot with video-corder monitoring system, import Hamilton microsyringe.
Laboratory animal: inbred line BALB/c, C57BL/6 mice, male, 20-22g, the SPF level is available from Chinese Academy of Sciences's Shanghai Experimental Animal Center.
2. method
2.1 medicine injecting method
The mouse peritoneal injection.
2.2 mice strides the mensuration of running property of lattice and unusual repeatability index
Mice after the administration is put into Flex-Field System, and system writes down the mice lattice situation of running of striding at the appointed time automatically; Start simultaneously and shoot with video-corder monitoring system, the record behavior of mice in the corresponding time down, watch videotape, the persistent period of unusual repetitive such as turn-taking, significantly shake the head among a small circle original place, rolls about in the original place appears in accumulative total mice within a certain period of time, and the time that calculates unusual palikinesia accounts for the percentage ratio that all shoot with video-corder the time.
2.3 mice strides the date processing of running property of lattice and unusual repeatability index
Striding the lattice linearity curve of running is abscissa with time, is vertical coordinate with the lattice number of times summations of striding of per 5 minutes mices.
Unusual repeated curve is abscissa with time, and the persistent period (s) of doing repetitive with mice in per 5 minutes the 1st minute is a vertical coordinate.
Data statistical approach: conventional T method of inspection.
Embodiment 1
The foundation of similar schizophrenia disease mouse model
To the MK801 of BALB/c mouse injection variable concentrations, matched group is a normal saline.
The result who strides running property of lattice (Fig. 1 and table 1) and repeated unusually (Fig. 2 and table 2) shows: MK801 can make BALB/c mouse produce the Deviant Behavior that is different from matched group.When MK801 is low concentration (less than the 0.3mg/kg body weight), along with the increase of concentration, mice strides the lattice quickening of running; During high concentration (greater than the 1.0mg/kg body weight), along with the increase of concentration, mice strides lattice and runs slack-off.For unusual repeated, along with the increase of MK801 concentration, its performance aggravation (the unusual repeated of normal saline group is 0).When MK801 concentration was the 0.3-1.0mg/kg body weight, mice strode lattice and runs and accelerate to repeat unusually also to aggravate simultaneously, shows comparatively typical the symptoms of schizophrenia.
Stride lattice data (striding the lattice number of times) the time MK801 dosage (mg/kg body weight) of running behind the table 1 BALB/c mouse injection MK801
Saline (min) 0.15 0.3 0.6 1.0 2.015 29.33 45.60 100.60 112.30 108.30 13.00
±10.66 ±12.56 ±17.68** ±17.70** ±21.87** ±3.9730 29.50 47.60 109.00 144.70 107.30 26.33
±10.94 ±17.06 ±21.61** ±26.12** ±21.78** ±9.8245 37.50 45.40 109.00 139.70 109.80 33.00
±11.27 ±23.19 ±18.38** ±25.57** ±20.94* ±9.9660 27.17 46.20 69.80 155.70 90.75 48.00
±10.51 ±26.22 ±20.85 ±14.94*** ±32.74 ±10.6175 22.00 28.20 78.80 143.00 104.80 58.67
±14.20 ±17.72 ±13.73* ±9.59*** ±22.45* ±8.96*90 21.50 25.40 38.20 111.70 74.00 67.89
±11.66 ±13.49 ±13.61 ±25.75** ±25.00 ±8.66**105 25.80 20.00 24.25 77.00 41.00 88.38
±16.26 ±11.70 ±18.25 ±24.58 ±22.37 ±12.00**120 16.00 13.40 22.60 71.83 46.50 111.60
± 12.00 ± 10.08 ± 11.38 ± 22.69 ± 24.62 ± 16.89** annotates: data are in the table: average ± SE* p＜0.05 is compared variant with the normal saline matched group; * p＜0.01 compares with the normal saline matched group that there were significant differences; Utmost point significant difference has been compared with the normal saline matched group in * * p＜0.001.
Unusual repetitive data (cumulative time) time MK801 dosage (mg/kg body weight) behind the table 2 BALB/c mouse injection MK801 is saline 0.15 0.3 0.6 1.0 2.015 00 0.1450 2.499 2.265 4.313 (min)
±0.09905 ±0.9163* ±0.9496* ±1.056**30 0 0 0.1460 5.086 4.692 3.245
±0.07496** ±1.870** ±1.645** ±0.8063**45 0 0 0 3.616 4.259 4.424
±1.252** ±1.567** ±0.4898***60 0 0.0380 0 2.197 0.7544 4.457
±0.03800 ±1.016* ±0.4040* ±0.4265***75 0 0 0 0.7767 0.1013 4.368
±0.4695 ±0.07310 ±0.6485***90 0 0 0 0.3601 0 2.917
±0.2202 ±0.4287***105 0 0 0 0.09056 0 2.362
±0.09056 ±0.2759***120 0 0 0 0 0 2.117
± 0.3347*** annotates: data are in the table: average ± SE* p＜0.05 is compared variant with the normal saline matched group; * p＜0.01 compares with the normal saline matched group that there were significant differences; Utmost point significant difference has been compared with the normal saline matched group in * * p＜0.001.
Embodiment 2
Mice (C57BL/6) with different strains is verified the similar schizophrenia disease mouse model of setting up
Give the MK801 of C57BL/6 injected in mice variable concentrations.
Result such as Fig. 3 shown in Fig. 4 and table 3 and the table 4, can produce similar schizoid symptom equally.Be that MK801 can make the C57BL/6 mice produce the Deviant Behavior that is different from matched group.When MK801 is low concentration (less than the 0.3mg/kg body weight), along with the increase of concentration, mice strides the lattice quickening of running; During high concentration (greater than the 1.0mg/kg body weight), along with the increase of concentration, mice strides lattice and runs slack-off.For unusual repetitive, along with the increase of MK801 concentration, its performance aggravation (the unusual repetitive of normal saline group is 0).When MK801 concentration was the 0.3-1.0mg/kg body weight, mice strode lattice and runs and accelerate simultaneously unusual repetitive and also aggravate, and shows comparatively typical the symptoms of schizophrenia.
The lattice of striding behind the table 3 C57BL/6 injected in mice MK801 are run data (the striding the lattice number of times) time
MK801 dosage (mg/kg body weight) is saline 0.15 0.3 0.6 1.0 2.015 55.10 68.7 91.5 78.56 46.89 12.4 (min)
±5.549 ±10.84 ±19.17 ±13.6 ±7.37 ±3.98***30 59.90 71 136.9 74.56 59.11 25.8
±3.195 ±13.34 ±23.69*** ±6.564 ±3.195 ±8.87245 50.8 72.2 160.3 112.2 54.22 34
±6.936 ±15 ±26.77*** ±10.07***?±4.627 ±9.01860 32.5 57.3 129.9 151.8 52.67 46.7
±6.529 ±11.55 ±28.57* ±16.54***?±8.268 ±9.57975 42.1 55.4 103.3 196.8 70.89 57.5
±6.047 ±7.521 ±26.51* ±17.37***?±11.89* ±7.77490 26.3 32 71.38 189.6 112 70.9
±8.912 ±9.597 ±19.76* ±18.91***?±13.79*** ±8.561**105 11 23.4 34 171.3 148.7 106.0
±5.292 ±14.38 ±8.805* ±25.55***?±20.15*** ±17.95***120 4.3 4 19.25 109.3 158.8 113.8
± 2.883 ± 3.89 ± 3.847 ± 35.53** ± 17.18*** ± 15.35*** annotates: data are in the table: average ± SE* p＜0.05 is compared variant with the normal saline matched group; * p＜0.01 compares with the normal saline matched group that there were significant differences; Utmost point significant difference has been compared with the normal saline matched group in * * p＜0.001.
Unusual repetitive data (cumulative time) time MK801 dosage (mg/kg body weight) behind the table 4 C57BL/6 injected in mice MK801 is saline 0.15 0.3 0.6 1.0 2.015 0 0.0870 1.479 5.056 2.950 3.491 (min)
±0.05406 ±0.3544*** ±1.346** ±0.5436*** ±0.5932***30 0 0.1030 1.059 2.976 3.550 3.837
±0.1030 ±0.1888*** ±0.3905***?±0.8040*** ±0.5817***45 0 0 0.6833 3.349 3.703 3.126
±0.2845* ±0.4500***?±1.0460*** ±0.3209***60 0 0 0.4211 2.725 2.738 2.940
±0.1571* ±0.3359***?±0.5805*** ±0.4305***75 0 0 0.1972 1.560 2.962 3.542
±0.09994 ±0.2677***?±0.4636*** ±0.5028***90 0 0 0.03500 1.123 2.593 3.519
±0.03500 ±0.2534***?±0.2490*** ±0.3711***105 0 0 0.07778 0.9950 1.525 2.642
±0.07778 ±0.1910***?±0.2236*** ±0.3110***120 0 0 0 0.5040 1.048 2.338
± 0.2370* ± 0.08966*** ± 0.3124*** annotates: data are in the table: average ± SE* p＜0.05 is compared variant with the normal saline matched group; * p＜0.01 compares with the normal saline matched group that there were significant differences; Utmost point significant difference has been compared with the normal saline matched group in * * p＜0.001.
Embodiment 3
Verify similar schizophrenia disease mouse model and tentatively set up related drugs screening platform with the schizoid medicine of treatment
In the present embodiment, inject the schizoid medicine Risperidone of current clinical treatment etc. to experiment mice, the MK801 of injection 0.6mg/kg body weight does the detection and the analysis of striding running property of lattice and unusual repeatability index immediately behind the some minutes.The result is shown in Fig. 5-6 and table 5-6, and Risperidone is striden running property of lattice and the unusual repeated inhibitory action that all has in various degree to model mice, and this inhibitory action and concentration is proportionate, and is the suitableeest scope with 0.05-0.25mg/kg body weight concentration.
Table 5 Risperidone acts on strides lattice data (striding the lattice number of times) the time MK801 Risperidone dosage (mg/kg body weight) (min) 0.05 0.1 0.2515 22.13 27.60 8.500 4.700 of running behind the schizophrenia disease mouse model
±7.735 ±14.80 ±6.030 ±2.821*30 23.75 7.100 4.500 1.100
±6.974 ±4.119* ±3.121* ±0.5260**45 52.00 14.20 6.900 0.800
±8.394 ±7.633** ±3.680*** ±0.4899***60 73.00 19.20 22.80 0.800
±4.200 ±8.349***?±7.777*** ±0.4899***75 80.00 34.20 46.90 0***
±12.12 ±14.96* ±10.3490 105.5 45.60 50.30 0.900
±11.12 ±14.55** ±9.358** ±0.348***105 105.9 50.60 51.80 2.100
±11.40 ±18.34* ±11.77** ±1.779***120 75.13 75.50 53.90 1.200
± 10.89 ± 17.44 ± 11.00 ± 0.5121*** annotates: data are in the table: average ± SE* p＜0.05 is compared variant with the MK801 model group; * p＜0.01 compares with the MK801 model group that there were significant differences; Utmost point significant difference has been compared with the MK801 model group in * * p＜0.001.
Table 6 Risperidone acts on (min) the 0.6mg/kg body weight 0.05 0.1 0.25 of unusual repetitive data (cumulative time) time MK801 Risperidone dosage (mg/kg body weight) behind the schizophrenia disease mouse model
3.165 1.769 1.065 0.562515
±0.5347 ±0.3671* ±0.2687** ±0.3287*
3.522 2.473 1.325 0.511330
±0.6593 ±0.5758 ±0.3053** ±0.5113*
2.707 1.953 1.795 0.540045
±0.6008 ±0.7616 ±0.3825 ±0.3119*
1.759 0.6715 0.8305 0.345060
± 0.3423 ± 0.3360* ± 0.2524* ± 0.2078* annotates: data are in the table: average ± SE* p＜0.05 is compared variant with the MK801 model group; * p＜0.01 compares with the MK801 model group that there were significant differences; Utmost point significant difference has been compared with the MK801 model group in * * p＜0.001.
Embodiment 4
Utilize schizophrenia drug checking medicine sorting platform effectiveness
Press embodiment 3 described methods, medicine sorting platform is verified, difference only is to replace Risperidone with the schizoid medicine olanzapine of current clinical treatment (Olanzapine).
Experimental result shows that medicine olanzapine (Olanzapine) can induce the symptom of generation to play the effect of alleviating even eliminating to MK801.Mouse model and Spirit of Man Split disease that this further proof has been set up exist dependency really.
Utilize schizophrenia drug screening platform screening drug candidate
In the present embodiment, give experiment mice injectable drug GNTI (molecular formula C
27H
29N
5O
32HCl), the MK801 of injection 0.6mg/kg body weight does the detection and the analysis of striding running property of lattice and unusual repeatability index immediately after 10 minutes.The result shows, GNTI strides running property of lattice and the unusual repeated inhibitory action that has in various degree to model mice, and this inhibitory action and concentration is proportionate, and is the suitableeest scope with 3.0-6.0mg/kg body weight concentration, and this shows that GNTI can be used as schizophrenia drug.
Discuss
The Spirit of Man behavior is unusual complicated, is subjected to many factor affecting, and the effect of exopathogenic factor and endogenous cause of ill is arranged, and directly studies mental sickness on the mankind's basis, is subjected to the influence of many factors such as ethics, statistics and non-operability.Set up the mental sickness animal model with laboratory animal, the complexity of real disease is simplified to concrete, controllable influence factor, for understanding and illustrating the mental sickness pathogenesis, the diagnosis index that quantizes mental sickness is significant; In drug screening or new drug evaluation, also will play a role simultaneously, become the important tool of new drug development.
Before this, have and induce rat can produce the report of similar the symptoms of schizophrenia, but do not set up animal pattern based on this with MK801.The author has proved not only that by a large amount of experiments this medicine has similar effect to mice, but also set up method and the data processing means that running property of lattice and unusual repeated two indexs are striden in a whole set of monitoring, schizoid symptom is quantized, make the performance of corelation behaviour obtain more objective reaction.Simultaneously, found MK801 to bring out the schizoid optimum concentration scope of experiment mice thus: the 0.3-1.0mg/kg body weight.
Experiment mice because of its genomic constitution research basis good and with human inheritance's homology, particularly the behavior of central nervous system's guidance has the comparability of height with human a large amount of neural activities, becomes the first-selected laboratory animal that has the incomparable superiority of other experiment materials in this research.There are a lot of different strains again in experiment mice, and their source and genetic background all have difference in various degree, and also performance differs in behavioristics.Yet, give the injected in mice MK801 of different strains, similar the symptoms of schizophrenia has but all appearred, and obtain similar experimental result, thereby further proved the effectiveness and the repeatability of this animal model.But because the difference (to the sensitivity difference of medicine) between the animal strain induces schizoid optimum concentration may have certain difference.
By striding the monitoring of running property of lattice and unusual repeated these two indexs, the inventor finds to inject after the MK801, and schizoid symptom has appearred being similar in mice.Because animal model only is the simulation of human diseases, therefore the model of being set up has been carried out further checking with schizoid medicine Risperidone of current clinical treatment and olanzapine.Experimental result shows the effect that these medicines all can induce the symptom of generation to play to alleviate even eliminate to MK801, thereby further mouse model and the Spirit of Man Split disease set up of proof exists dependency really.
Schizophrenia drug screening platform of the present invention can be used for screening new drug and exploitation other treatment method.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. method of setting up schizophrenia mammal model is characterized in that it comprises step:
Give 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt of described administration schizophrenia effective dose.
2. the method for claim 1 is characterized in that, described animal is mice or rat.
3. the method for claim 1 is characterized in that, uses 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt by intraperitoneal injection.
4. method according to claim 1 is characterized in that described schizophrenia effective dose is a 0.05-5 mg/kg body weight.
5. as method as described in the claim 4, it is characterized in that described schizophrenia effective dose is a 0.1-2.5 mg/kg body weight.
6. as method as described in the claim 5, it is characterized in that described schizophrenia effective dose is a 0.15-2 mg/kg body weight.
7. a method of screening the psychosis medicine is characterized in that, comprises step:
(a) material standed for is applied to mammal with 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt;
(b) observe mammiferous schizophrenia characteristic behavior, wherein, the decline of the schizophrenia characteristic behavior frequency of occurrences and/or amplitude just represents that this material standed for is the psychosis medicine.
8. method as claimed in claim 7 is characterized in that, described schizophrenia characteristic behavior comprises strides running property of lattice and repeated unusually.
9. method as claimed in claim 7 is characterized in that, in the step (a), also comprises material standed for or MK801 are applied to mammal respectively separately.
10. method as claimed in claim 7 is characterized in that, in the step (a), the amount of application of 5-methyl dihydro-dibenzo cycloheptene imido maleic acid or its salt is a 0.05-5 mg/kg body weight.
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